VARILRIX 10^33 PFU/0.5ML POWDER AND SOLVENT FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Varilrix powder and solvent for solution for injection in pre-filled syringe

Varicella vaccine (live)

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

After reconstitution, one dose (0.5 mL) contains:

Varicella virus1 Oka strain (live, attenuated) not less than 103.3 PFU2

1 produced in human diploid cells (MRC-5)

2 plaque forming units

This vaccine contains a trace amount of neomycin (see section 4.3).

Excipients with known effect:

The vaccine contains 6 mg of sorbitol per dose.

The vaccine contains 331 micrograms of phenylalanine per dose (see section 4.4).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for injection in pre-filled syringe.

Before reconstitution, the powder is slightly cream to yellowish or pinkish coloured cake and the solvent is a clear colourless liquid.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Varilrix is indicated for active immunisation against varicella of healthy subjects (from the age of 9 months).

Vaccination of susceptible healthy close contacts of subjects at risk of severe varicella is recommended, in order to reduce the risk of transmission of wild-type virus to these patients. Close contacts include parents and siblings of high-risk patients, and medical and paramedical personnel.

4.2 Posology and method of administration

Posology

The immunisation schedules for Varilrix should be based on official recommendations.

Healthy individuals

Infants from 9 months to 11 months of age (inclusive)

Infants from 9 to 11 months of age (inclusive) receive two doses of Varilrix to ensure optimal protection against varicella (see section 5.1). The second dose should be given after a minimum interval of 3 months.

Children from 12 months of age, adolescents and adults

Children from the age of 12 months as well as adolescents and adults receive two doses of Varilrix to ensure optimal protection against varicella (see section 5.1). The second dose should generally be given at least 6 weeks after the first dose. Under no circumstances should the interval between the doses be less than 4 weeks.

Individuals at high risk of severe varicella

Individuals at high risk of severe varicella may benefit from re-vaccination following the 2-dose schedule (see section 5.1). Periodic measurement of varicella antibodies after immunisation may be indicated in order to identify those who may benefit from re-immunisation. Under no circumstances should the interval between the doses be less than 4 weeks.

Other , paediatric , population

The safety and efficacy of Varilrix in infants less than 9 months of age have not yet been established. No data are available.

Interchangeability

– A single dose of Varilrix may be administered to those who have already received a single dose of another varicella-containing vaccine.

– A single dose of Varilrix may be administered followed by a single dose of another varicella-containing vaccine.

Method of administration

Varilrix is to be injected subcutaneously (SC) or intramuscularly (IM) in the deltoid region or in the anterolateral area of the thigh.

Varilrix should be administered subcutaneously in individuals with bleeding disorders (e.g. thrombocytopenia or any coagulation disorder).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindi­cations

Varilrix is contraindicated in individuals with severe humoral or cellular (primary or acquired) immunodeficiency such as (see also section 4.4.):

– subjects with immunodeficiency states with a total lymphocyte count less than 1,200 per mm3;

– subjects presenting other evidence of lack of cellular immune competence (e.g. patients with leukaemias, lymphomas, blood dyscrasias, clinically manifest HIV infection);

– subjects receiving immunosuppressive therapy including high dose of corticosteroids;

– severe combined immunodeficiency;

– agammaglobulinemia;

– AIDS or symptomatic HIV infection or an age-specific CD4+ T-lymphocyte percentage in children below 12 months: CD4+ <25%; children between 12–35 months: CD4+ < 20%; children between 36–59 months: CD4+ < 15%.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to neomycin. However, a history of contact dermatitis to neomycin is not a contraindication.

Varilrix is contraindicated in subjects having shown signs of hypersensitivity after previous administration of varicella vaccine.

Pregnancy. Furthermore, pregnancy should be avoided for 1 month following vaccination (see section 4.6).

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

As with other vaccines, the administration of Varilrix should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

Syncope (fainting) can occur following, or even before, any vaccination especially in adolescents as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints.

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic reaction following the administration of the vaccine.

Alcohol and other disinfecting agents must be allowed to evaporate from the skin before injection of the vaccine since they can inactivate the attenuated viruses in the vaccine.

Limited protection against varicella may be obtained by vaccination up to 72 hours after exposure to natural disease (see section 5.1).

As with any vaccine, a protective immune response may not be elicited in all vaccinees.

As for other varicella vaccines, cases of varicella disease have been shown to occur in persons who have previously received Varilrix. These breakthrough cases are usually mild, with a fewer number of lesions and less fever as compared to cases in unvaccinated individuals.

Transmission

Transmission of the Oka varicella vaccine virus has been shown to occur at a very low rate in seronegative contacts of vaccinees with rash. Transmission of the Oka varicella vaccine virus from a vaccinee who does not develop a rash to seronegative contacts cannot be excluded.

Compared to healthy vaccinees, leukaemia patients are more likely to develop a papulovesicular rash (see also section 4.8). In these cases too, the course of the disease in the contacts was mild.

Vaccine recipients, even those who do not develop a varicella-like rash, should attempt to avoid contact, whenever possible, with high-risk individuals susceptible to varicella for up to 6 weeks following vaccination. In circumstances where contact with high-risk individuals susceptible to varicella is unavoidable, the potential risk of transmission of the varicella vaccine virus should be weighed against the risk of acquiring and transmitting wild-type varicella virus.

High-risk individuals susceptible to varicella include:

– Immunocompromised individuals (see sections 4.3 and 4.4);

– Pregnant women without documented positive history of varicella (chickenpox) or laboratory evidence of prior infection;

– Newborns of mothers without documented positive history of chickenpox or laboratory evidence of prior infection.

The mild nature of the rash in the healthy contacts indicates that the virus remains attenuated after passage through human hosts.

Individuals at high risk of severe varicella

There is only limited data from clinical trials available for Varilrix (+4°C formulation) in individuals at high risk of severe varicella.

Vaccination may be considered in patients with selected immune deficiencies where the benefits outweigh the risks (e.g. asymptomatic HIV subjects, IgG subclass deficiencies, congenital neutropenia, chronic granulomatous disease, and complement deficiency diseases).

Immunocompromised patients who have no contraindication for this vaccination (see section 4.3) may not respond as well as immunocompetent subjects, therefore some of these patients may acquire varicella in case of contact, despite appropriate vaccine administration. These patients should be monitored carefully for signs of varicella. Should vaccination be considered in individuals at high risk of severe varicella, it is advised that:

– maintenance chemotherapy should be withheld one week before and one week after immunisation of patients in the acute phase of leukaemia. Patients under radiotherapy should normally not be vaccinated during the treatment phase. Generally, patients are immunised when they are in complete haematological remission from their disease.

– the total lymphocyte count should be at least 1,200 per mm3 or no other evidence of lack of cellular immune competence exists.

– vaccination should be carried out a few weeks before the administration of the immunosuppressive treatment for patients undergoing organ transplantation (e.g. kidney transplant).

Very few reports exist on disseminated varicella with internal organ involvement following vaccination with Oka varicella vaccine strain mainly in immunocompromised subjects.

Varilrix must not be administered intravascularly or intradermally.

Phenylalanine content

The vaccine contains 331 micrograms of phenylalanine per dose. Phenylalanine may be harmful for individuals with phenylketonuri­a (PKU).

4.5 Interaction with other medicinal products and other forms of interaction If tuberculin testing has to be done it should be carried out before or simultaneously with vaccination since it has been reported that live viral vaccines may cause a temporary depression of tuberculin skin sensitivity. As this anergy may last up to a maximum of 6 weeks, tuberculin testing should not be performed within that period after vaccination to avoid false negative results.

In subjects who have received immune globulins or a blood transfusion, vaccination should be delayed for at least three months because of the likelihood of vaccine failure due to passively acquired antibody to the varicella-zoster virus.

Aspirin and systemic salicylates should not be given to children under the age of 16, except under medical supervision, because of the risk of Reye’s syndrome. Reye’s syndrome has been reported in children treated with aspirin during natural varicella infection. However, there is no evidence to suggest that vaccination with Varilrix should be contraindicated for older age-groups who need to take aspirin.

In a study in which Varilrix was administered to toddlers at the same time as, but at a different site to, a combined measles, mumps and rubella vaccine, there was no evidence of significant immune interference between the live viral antigens.

If a measles containing vaccine is not given at the same time as Varilrix, it is recommended that an interval of at least one month between vaccinations is respected, since it is recognised that measles vaccination may cause short-term suppression of the cell-mediated response.

If it is considered necessary to administer another live vaccine at the same time as Varilrix, the vaccines must be given as separate injections and at different body sites.

4.6 Fertility, pregnancy and lactation

Pregnancy

Pregnant women should not be vaccinated with Varilrix.

However, fetal damage has not been documented when varicella vaccines have been given to pregnant women.

Pregnancy should be avoided for 1 month following vaccination. Women who intend to become pregnant should be advised to delay.

Breast-feeding

The infants of seronegative women would not have acquired transplacental antibody to varicella-zoster virus. Therefore, due to the theoretical risk of transmission of the vaccine viral strain from mother to infant, women should not be vaccinated while breastfeeding.

Fertility

No fertility data are available

4.7 Effects on ability to drive and use machines

It would not be expected that vaccination would affect the ability to drive or operate machinery.

4.8 Undesirable effects

Clinical trials in healthy subjects

More than 7,900 individuals have participated in clinical trials evaluating the reactogenicity profile of the vaccine administered alone or concomitantly with other vaccines.

The safety profile presented below is based on a total of 5369 doses of Varilrix administered alone to children, adolescents and adults.

The most common adverse reactions observed after vaccine administration were injection site pain (23.8%), redness (19.9%) and swelling (12.1%).

Frequencies are reported as:

Very common:        >1/10

Common:            >1/100 and <1/10

Swelling at the injection site and fever were very commonly reported in studies conducted in adolescents and adults. Swelling was also reported very commonly after the second dose in children under 13 years of age.

A trend for higher incidence of pain, redness and swelling after the second dose was observed as compared to the first dose.

No differences were seen in the reactogenicity profile between initially seropositive and initially seronegative subjects.

Post-marketing surveillance

During post-marketing surveillance, the following additional reactions have been reported after varicella vaccination:

Transmission of the vaccine virus from healthy vaccines to healthy contacts has been shown to occur very rarely.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Cases of accidental administration of more than the recommended dose of Varilrix have been reported. Amongst these cases, the following adverse events were reported: lethargy and convulsions. In other cases, no associated adverse events were reported.

5 PHARMACOLOGICAL PROPERTIES

ATC code J07B K01

The Oka strain virus contained in Varilrix was initially obtained from a child with natural varicella; the virus was then attenuated through sequential passage in tissue culture.

Natural infection induces a cellular and humoral immune response to the varicellazoster virus, which can be rapidly detected following infection. IgG, IgM and IgA directed against viral proteins usually appear at the same time that a cellular immune response can be demonstrated, making the relative contribution of humoral and cellular immunity to disease progression difficult to ascertain. Vaccination has been shown to induce both humoral and cell-mediated types of immunity.

Efficacy and effectiveness

The efficacy of GlaxoSmithKline (GSK)’s monovalent Oka (Varilrix) and PriorixTetra vaccines in preventing varicella disease has been evaluated in a large randomised multicountry clinical trial, which included GSK combined measlesmumps-rubella vaccine, Priorix as control. The trial has been conducted in European countries where no routine varicella vaccination is implemented.

Children aged 12–22 months received two doses of combined measles, mumps, rubella and varicella vaccine six weeks apart or one dose of Varilrix. Vaccine efficacy against confirmed varicella of any severity and against moderate or severe confirmed varicella was demonstrated after a primary follow-up period of 2 years (median duration 3.2 years). Persistent efficacy was observed in the same study during the long term follow-up periods of 6 years (median duration 6.4 years) and 10 years (median duration 9.8 years). The data are presented in the table below.

N = number of subjects enrolled and vaccinated

(1) descriptive analysis

The effectiveness of one dose of Varilrix was estimated in different settings (outbreaks, case-control and database studies) and ranged from 20%-92% against any varicella disease and from 86%-100% against moderate or severe disease.

The impact of one dose of Varilrix in reducing varicella hospitalizations and ambulatory visits among children were respectively 81% and 87% overall.

Effectiveness data suggest a higher level of protection and a decrease in breakthrough varicella following two doses of vaccine than following one dose.

In clinical trials that enrolled 211 adolescents and 213 adults, all vaccinees had detectable levels of antibodies in blood samples taken six weeks after the second vaccine dose. Virtually all (98.7%) of the 1637 children tested had detectable antibodies six weeks after immunisation with one dose of vaccine.

Virtually all (>98.7%) children aged 9 months to 12 years tested had antibody levels > 4 (dil-1) six weeks after immunisation with one dose of Varilrix.

All of 659 children aged 9 months to 6 years, who received a second dose of Varilrix or received Varilrix after a first dose of another varicella vaccine, had antibody levels > 4 (dil-1) at 6–18 weeks following vaccination. There was a large increase in GMT (up to 13-fold) between post-dose 1 and post-dose 2.

However, the safety and immunogenicity of a second dose of Varilrix in adolescents (>13 years) and adults primed with another varicella-containing vaccine has not been specifically studied in clinical trials.

In a follow-up study over 2 years in 159 vaccinated adult health care workers, 2 out of 72 (3%) vaccinees reporting contacts with wild-type chickenpox experienced mild breakthrough disease. Approximately one-third of the vaccinees showed an increase in antibody titre over the follow-up period, indicative of contact with the virus, without clinical evidence of varicella infection.

The percentage of vaccinees who will later experience herpes-zoster due to reactivation of the Oka strain virus is currently unknown. However, the risk of zoster after vaccination is currently thought to be much lower than would be expected after wild-type virus infection, due to attenuation of the vaccine strain.

5.2 Pharmacokinetic properties

Evaluation of pharmacokinetic properties is not required for vaccines.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder

Amino acids (containing phenylalanine)

Lactose anhydrous

Sorbitol (E 420)

Mannitol (E 421)

Solvent

Water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years.

After reconstitution, it is recommended that the vaccine be injected as soon as possible.

However, it has been demonstrated that the reconstituted vaccine may be kept for up to 90 minutes at room temperature (25°C) and up to 8 hours in the refrigerator (2°C to 8°C). If not used within the recommended in-use storage timeframes and conditions, the reconstituted vaccine must be discarded.

6.4 Special precautions for storage

Store and transport refrigerated (2°C to 8°C).

Store in the original package in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Powder in a single-dose glass vial (type I glass) with a stopper (bromobutyl rubber).

0.5 ml of solvent in a pre-filled syringe (type I glass) with plunger stopper (bromobutyl rubber), with or without separate needles in the following pack sizes: – with 1 separate needle: pack sizes of 1 or 10.

– with 2 separate needles: pack sizes of 1 or 10.

– without needle: pack sizes of 1 or 10.

0.5 ml of solvent in an ampoule (type I glass).

Pack size of 10.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The solvent and the reconstituted vaccine should be inspected visually for any foreign particulate matter and/or abnormal physical appearance before administration. In the event of either being observed, do not administer the vaccine.

The vaccine must be reconstituted by adding the entire contents of the pre-filled syringe or ampoule of solvent to the vial containing the powder.

To attach the needle to the syringe, carefully read the instructions given with pictures

1 and 2. However, the syringe provided with Varilrix might be slightly different (without screw thread) than the syringe illustrated.

In that case, the needle should be attached without screwing.

Needle

Needle hub

Syringe plunger

Luer Lock Adaptor

Syringe barrel

Syringe cap

Picture 1

Picture 2

Always hold the syringe by the barrel, not by the syringe plunger or the Luer Lock Adaptor (LLA), and maintain the needle in the axis of the syringe (as illustrated in picture 2). Failure to do this may cause the LLA to become distorted and leak.

During assembly of the syringe, if the LLA comes off, a new vaccine dose (new syringe and vial) should be used.

1. Unscrew the syringe cap by twisting it anticlockwise (as illustrated in picture 1).

Whether the LLA is rotating or not, please follow the below steps:

2. Attach the needle to the syringe by gently connecting the needle hub into the LLA and rotate a quarter turn clockwise until you feel it lock (as illustrated in picture 2).

3. Remove the needle protector, which may be stiff.

4. Add the solvent to the powder. The mixture should be well shaken until the powder is completely dissolved in the solvent.

The colour of the reconstituted vaccine may vary from clear peach to pink due to minor variations of its pH. This is normal and does not impair the performance of the vaccine. In the event of other variation being observed, do not administer the vaccine.

5. Withdraw the entire contents of the vial.

6. A new needle should be used to administer the vaccine. Unscrew the needle from the syringe and attach the injection needle by repeating step 2 above.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

SmithKline Beecham Ltd

980, Great West Road

Brentford

Middlesex TW8 9GS

United Kingdom

GlaxoSmithKline UK